Cognitive decline, such as memory loss, confusion, impaired judgment, personality changes, disorientation, and loss of language skills occurs in much of the population as they age, in varying degree. The most common, severe and irreversible form of cognitive decline is Alzheimer's disease, which, at present, is always fatal.
The symptoms of cognitive decline and Alzheimer's disease are thought to stem from the formation of amyloid plaques and neurofibrillary tangles, which are thought to contribute to the degradation of the neurons (nerve cells) in the brain and the subsequent onset of symptoms. Amyloid is a general term for protein fragments that the body produces normally. Beta-amyloid is a fragment of a protein that is snipped from another protein called amyloid precursor protein (APP). In a healthy brain, beta-amyloid protein fragments are broken down and eliminated. In individuals with Alzheimer's disease and other forms of cognitive decline, the fragments accumulate to form hard, insoluble plaques. Neurofibrillary tangles are insoluble twisted fibers that are found inside of the brain's cells. The protein contained in neurofibrillary tangles, i.e., the tau protein, forms a microtubule, which helps transport nutrients and other important substances from one part of the nerve cell to another. In Alzheimer's disease the tau protein is abnormal and the microtubule structures collapse.
Beta-secretase is the enzyme in the human brain responsible for the production of Beta-amyloid, the pathogenic substance responsible for the formation of brain plaques and tangles in the Alzheimer's diseased brain. See, e.g., Citron et al., Proc. Natl. Acad. Sci., USA (1996) 93(23): 13170-13175. Beta-amyloid and its oligomers are also believed to be responsible for early cognitive decline in the pre-Alzheimer's diseased brain. Inhibition of beta-secretase would be expected to lessen beta-amyloid burden in the brain and thus slow cognitive decline, block the formation of amyloid oligomers, the production of plaques and tangles, halt neurodegeneration, and to potentially treat mild cognitive impairment and more serious forms of cognitive impairment such as Alzheimer's disease.
The gingerols are a series of natural small molecules isolated from ginger, Zingiber Officinale, and are classified according to their alkyl chain length e.g., [6]-gingerol, [8]-gingerol. Gingerols are known to be relatively unstable under both chemical and biological conditions, forming inactive substances. For example, the beta-hydroxycarbonyl function of the gingerols is vulnerable to oxidation or dehydration to form inactive products, and the gingerols are particularly prone to rapid dehydration under acidic conditions, such that even the pure substance is difficult to store for long periods. Further information on gingerols can be found in, for example, Deniff et al., J. Chem. Soc. Perkin I, 1981, 82-87; Mustafa, et al., J. Drug Dev., 1993, 6, 25-39; and Young-Joon et al., Life Sciences, 1994, 54, PL 321-326. Accordingly, simple oral dosing of the gingerols for medicinal action might not be possible due to the acidic environment of the stomach and upper intestinal tract. Further, chemical and biological instability is also likely to be a serious problem for intravenous doses. Accordingly, there is strong need to discover inhibitors of cognitive decline, and in particular, compounds that are useful in the treatment and abatement of cognitive decline and Alzheimer's disease, by methods such as inhibiting amyloid production, aggregation, and/or deposition (i.e., plaqing), inhibiting neuorodegeneration, and/or restoring long term potentiation. There is also a need for inhibitors of cognitive decline that are chemically and biologically stable.
Plants have attracted relatively little attention as potentially valuable resources for drug discovery in the area of cognitive decline and Alzheimer's disease. The use of plant extracts to produce unnatural derivatives of compounds of medicinal interest is not generally used. Accordingly, there is also a need for a method of producing compounds of medicinal interest from plant extracts and extracts from other biological sources. In particular, there is also a need to produce and identify compounds derived from plant extracts that are useful in the treatment and abatement of cognitive decline and Alzheimer's disease.